Exhaled nitric oxide (eNO) is a non-invasive marker for airway inflammation. Inflammation of the airways is present in patients with asthma, who produce elevated levels of NO in the lower respiratory tract (bronchi and alveolar part). Therefore, high values of eNO can be used in combination with other pulmonary tests for diagnosing asthma. Furthermore, eNO can be used for monitoring the effectiveness of inhaled corticosteroids (ICS) and in anti-inflammatory asthma management to titrate ICS dosage.
The standardized method of measuring eNO involves the subject participating in a single exhalation experiment in which they breathe out at a fixed flow rate of 50 ml/s and an overpressure of at least 5 cm H2O. Recommendations on a standardized method by the American Thoracic Society and European Respiratory Society are set out in the paper “ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005” American Journal of Respiratory and Critical Care Medicine Vol. 171, pp 912-930 2005.
An exemplary apparatus for performing a fixed flow rate measurement is shown in FIG. 1. The apparatus 2 comprises a tube 3 arranged in a generally ‘Y’ shape with the three ends forming an air inlet 4, an air outlet 6 and a mouthpiece 8 respectively. A first one-way valve 10 is provided in the tube 3 between the air inlet 4 and the mouthpiece 8 and a second one-way valve 12 is provided in the tube 3 between the mouthpiece 8 and the air outlet 6. The one-way valves 10, 12 are configured so that air is drawn through the tube 3 via the air inlet 4 and mouthpiece 8 when the subject inhales, and air is passed through the tube 3 via the mouthpiece 8 and air outlet 6 when the subject exhales.
The apparatus 2 also comprises a sensor 14 for measuring levels of NO in the exhaled air that is connected to a side stream 15 located between the second one-way valve 12 and the air outlet 6, and a pressure sensor 16 connected to a side stream 17 that is also located between the second one-way valve 12 and the air outlet 6. The pressure sensor 16 measures the pressure resulting from the exhalation of air through a flow restrictor 20 and provides audio and/or visual feedback to the subject on whether the flow and pressure of the exhaled air is appropriate for the measurement (i.e. a fixed flow rate of 50 ml/s and a pressure of at least 5 cm H2O) via a feedback device 18. A processor 19 is connected to the sensor 14 for processing the NO measurements to determine the NO level in the, or a portion of the, exhaled air.
The flow restrictor 20 is provided in the air outlet 6 to make it easier for the subject to reach the required flow and overpressure. Once the required pressure is achieved, the velum—the soft palate consisting of muscle fibers sheathed in mucous membrane responsible for closing off the nasal passages during the act of swallowing and sneezing—is closed preventing NO from the nasal cavity of the subject passing into the oral cavity.
A NO filter 22 can be provided in the tube 3 between the air inlet 4 and the first one-way valve 10 that removes NO from the air drawn into the apparatus 2 from the surrounding environment when the subject inhales.
However, a problem with this apparatus is that it requires a constant exhalation flow for a given period of at least 10 seconds, and this is not simple to perform, in particular for young children, older subjects, or subjects having difficulty breathing. Although commercial systems are available based on the apparatus shown in FIG. 1 that have received approval from the US Food and Drug Administration (FDA) for standardized eNO measurements on children aged 7-18 years and adults under supervision of a trained operator in a physician's office, there is currently no FDA-approved system for use in young children.
Techniques exist to measure an eNO value during oral tidal breathing by the subject. Tidal breathing is a much more straightforward and natural breathing process and thus is much simpler for the subject to perform than tests using single breath exhalations at a fixed flow or tests requiring a breath hold for a certain time. A tidal breathing manoeuvre can be performed by the subjects themselves without guidance and probably in cooperative children from the age of three onwards. Tidal breathing generally involves a breathing frequency of 4-20 breaths per minute for adults and 20-40 breaths per minute for children and exhaled volumes of 300-1000 ml per breath for adults and 100-500 ml for children.
However, a problem with tidal eNO measurement methods is that the increased flow rates (typically 100-500 ml/s) involved reduces the concentration of nitric oxide (NO) in the air at the sensor, which makes the measurement more sensitive to various disturbances like contamination from NO in the environment or NO from the nasal area of the subject.
This problem is related to two issues. Firstly, the standardized fixed flow rate manoeuvre starts with a deep inhalation while tidal breathing involves a shallower inhalation. This means that only some of the air from previous inhalations is exchanged in tidal breathing. Furthermore, during the shorter time involved in a tidal breathing cycle, the NO in the inhaled air is only partly removed by the alveoli in the subject's lungs. Therefore, even when NO-free air is inhaled through the mouth in a tidal breathing manoeuvre, some inhaled nasal NO can “contaminate” the exhaled air.
Secondly, during the exhalation in the standardized fixed flow rate manoeuvre, the velum is closed due to the overpressure, so no NO from the nasal cavity can pass into the oral cavity. However, during tidal exhalation the velum might be open and NO from the nasal cavity can diffuse into the air exhaled through the mouth.
Therefore, there is a need for a method and apparatus that measures NO in exhaled air during a tidal breathing manoeuvre in which at least some of the above mentioned disadvantages are mitigated.